Microglia are a resident population of phagocytic immune cells that reside within the central nervous system (CNS). During gestation, they are highly sensitive to their surrounding environment and can alter their physiology to respond to perceived neural insults, potentially leading to adverse influences on nearby neural progenitors. Given that bisphenol A (BPA) itself can impact developing brains, and that microglia express estrogen receptors to which BPA can bind, here we asked whether fetal microglia are responsive to gestational BPA exposure. Accordingly, we exposed pregnant dams to control or 50 mg of BPA per kg diet during gestation to investigate the impact of maternal BPA on embryonic hypothalamic microglia. Gestational BPA exposure from embryonic day 0.5 (E0.5) to E15.5 resulted in a significant increase in the number of microglia present in the hypothalamus of both male and female embryos. Staining for microglial activation using CD68 showed no change between control and prenatal BPA-exposed microglia, regardless of sex. Similarly, analysis of cultured embryonic brains demonstrated that gestational BPA exposure failed to change the secretion of cytokines or chemokines, regardless of embryo sex or the dose (50 μg of BPA per kg or 50 mg of BPA per kg maternal diet) of BPA treatment. In contrast, live-cell imaging of microglia dynamics in E15.5 control and gestationally-exposed BPA hypothalamic slices showed increased ramification of microglia exposed to BPA. Moreover, live-cell imaging also revealed a significant increase in the number of microglial phagocytic cups visible following exposure to gestational BPA. Together, these results suggest that gestational BPA exposure impacts embryonic hypothalamic microglia, perhaps leading them to alter their interactions with developing neural programs.
e12578 Background: The optimal local regional management of the positive axilla in patients who convert to clinical negative nodal status after neoadjuvant chemotherapy (NAC) remains unclear. Specifically, the benefit of completion axillary node dissection (cALND) remains in question, particularly given the associated morbidity. With results of the A11202 trial pending, we noted regional variation in the management of the axilla in this population. We therefore aimed to describe the current management of women with positive SNB after NAC, describe recurrence patterns and identify predictors of cALND in a large, population-based, real-world setting. Methods: We identified all patients who had biopsy-proven nodal disease on presentation, underwent NAC and were then clinically downstaged allowing SNB as part of their index surgery from our Synoptec provincial operative database, from January 2016 to September 2021. Pre and post NAC tumour characteristics, patient demographics, treatments and final pathology were abstracted and conveyed using descriptive statistics. Primary outcome measures were treatment with cALND and recurrence. A Cox regression model was utilized to determine predictors of both outcomes. Results: A total of 850 patients had biopsy-proven axillary disease at presentation and subsequently underwent NAC. Of these, 364 patients converted to clinically-negative node status and had a SNB, of which 175 (48%) had persistent nodal disease. Median age of this group was 50 (IQR 43-60) and 143 patients (81.7%) were treated by a high-volume breast surgeon. Most patients had clinical T1/2 tumours (73.1%) before NAC, of which 21.1% were HER2 positive, and 12.6% were triple-negative. Post NAC, 95 patients (54.3%) underwent mastectomy. A total of 39/175 patients (22.3%) underwent a cALND. Median number of sentinel nodes was 4 (IQR 3, 5); the proportion of positive sentinel nodes did not differ in those who had cALND (0.59 vs. 0.59, p = 0.95). Almost all patients (96.6%) had regional radiation. After a median of 17 months of follow-up, 33 (18.8%) SNB positive patients recurred; the majority (29 (87.9%)) had a distant recurrence, 3 (9.1%) had an isolated local breast/chest wall recurrence, and only 1 (3.0%) had an isolated regional recurrence. As far as local control, in patients with any regional recurrence, 4/7 (57.1%) had undergone cALND. Treatment site was the only significant predictor of cALND on multivariable analysis. Predictors of recurrence were low BMI, triple-negative status and clinical T3/4 disease before NAC. Conclusions: The lack of definitive data for patients with persistent pathologic nodal disease after NAC has led to variable practice patterns, with lower than expected rates of cALND. Within our cohort, there was not a significant association between omission of cALND and regional recurrence.
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